Without limiting the scope of the invention, its background is described in connection with existing treatments for pancreatic ductal adenocarcinoma (PDAC). PDAC is typically associated with drug resistance, metastasis, and dismal clinical outcomes. To date, surgery is the only treatment that offers patients with PDAC a chance for cure. See Hartwig W, et al. “Improvement of surgical results for pancreatic cancer” Lancet Oncol. 14 (2013) e476-85. Early detection of this stroma-rich, desmoplastic neoplasm is challenging because of long symptom-free intervals. See Olson P, Hanahan D. “Breaching the Cancer Fortress” Science. 324 (2009) 1400-1. Although extensive efforts have been made to advance the molecular and clinical understanding of PDAC, drug-based treatment regimens have been unsatisfactory so far, and 5-year survival has improved only slightly over the past decades.
PDAC is associated with several well-described mutations in a subset of genes including those that encode KRAS, SMAD4, and p53. See Morris J P, et al. “KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma” Nat Rev Cancer 10 (2010) 683-95. PDAC also exhibits additional mutations that affect various pathways. See Jones S, et al. “Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses” Science 321 (2008) 1801-6. Spontaneous genetic alterations make a successful treatment relatively difficult since they provide pancreatic tumors escape routes from therapy.
From the foregoing it is apparent the there is a need in the art for improved therapeutic regimens that are effectively directed to reducing the metastatic potential of cancer stem cells without adversely affecting normal stem cells.